19-7141764-G-C

Variant names:

• chr19-7141764-G-C
• rs2229431
• NM_000208.4:c.2595C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000208.4(INSR):​c.2595C>G​(p.Asn865Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N865N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.753
• Publications: 0 publications found

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

INSR Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency, Donohue syndrome, insulin-resistance syndrome type A.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29400605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.2595C>G	p.Asn865Lys	missense_variant	Exon 13 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2559C>G	p.Asn853Lys	missense_variant	Exon 12 of 21		NP_001073285.1
INSR	XM_011527988.3	c.2595C>G	p.Asn865Lys	missense_variant	Exon 13 of 22		XP_011526290.2
INSR	XM_011527989.4	c.2559C>G	p.Asn853Lys	missense_variant	Exon 12 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2595C>G	p.Asn865Lys	missense_variant	Exon 13 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2559C>G	p.Asn853Lys	missense_variant	Exon 12 of 21	1		ENSP00000342838.4
INSR	ENST00000597211.1	n.278C>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.2
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	.;D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.3	.;L
PhyloP100		-0.75
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.25
Sift	Benign	0.087	T;T
Sift4G	Uncertain	0.050	T;T
Polyphen		0.13	B;B
Vest4		0.50
MutPred		0.55		.;Gain of methylation at N865 (P = 0.0095);
MVP		0.80
MPC		0.91
ClinPred		0.32	T
GERP RS		-6.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.70
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2229431; hg19: chr19-7141775;